PROJECT SUMMARY Tuberculosis preventive therapy (TBPT) is among the most efficacious and cost-effective interventions to reduce tuberculosis (TB) incidence and mortality among people living with HIV (PLHIV) but is grossly underutilized due to our reliance on a symptom-based screening test to rule-out active TB. Studies from Africa have shown that symptom screening has low specificity (10-30%) for active TB and does not meet the minimum specificity (?70%) requirement established by the World Health Organization (WHO) for TB screening. The low specificity is a major barrier to TBPT scale-up because if current TB screening guidelines were followed, 70-90% of PLHIV without active TB would not only be denied immediate initiation of TBPT but would also require unnecessary and costly confirmatory TB testing. The overall objective of this application is to evaluate the impact of a potentially more effective and cost-effective TB screening strategy, which is the next step required for successful uptake of TBPT. Our central hypothesis is that compared to symptom screening, a TB screening strategy based on C-reactive protein (CRP) levels, measured using a point-of-care (POC) assay, will improve TBPT uptake, thereby reducing TB incidence and its associated mortality among PLHIV. The scientific premise for this hypothesis is based on our own work that identified POC CRP as the first tool to meet the minimum sensitivity (?90%) and specificity (?70%) targets established by the WHO for TB screening. To accelerate scale-up of this promising TB screening strategy, and thus scale-up of TBPT, we propose a single-center individual randomized trial to evaluate the impact of POC CRP-based TB screening in 1720 PLHIV initiating antiretroviral therapy from 3 prototypical HIV clinics in Uganda. Participants will be randomized to either POC CRP- or symptom-based TB screening and followed for 2-years. Aim 1 will determine whether POC CRP-based TB screening improves 2-year clinical outcomes. The primary outcome for Aim 1 will be a composite of TB incidence and all-cause mortality. Key secondary outcomes include TB- specific mortality and incidence of drug-resistant TB. Aim 2 will determine the impact of POC CRP-based TB screening on intermediate outcomes related to the primary trial outcome. Primary outcomes for Aim 2 include the proportion of PLHIV (a) initiating TBPT and (b) diagnosed with prevalent TB. Secondary outcomes include the proportion of PLHIV (a) completing TBPT and (b) completing treatment for prevalent TB. Aim 3 will compare the cost-effectiveness and projected epidemiologic impact of TB screening with and without POC CRP. CRP testing will be performed using a low-cost ($2 per test), rapid (3 minutes) and simple (measured from capillary blood) POC assay, increasing the likelihood that POC CRP-based TB screening will be implemented in even the most peripheral settings. This research is significant because in addition to quantifying the expected clinic, economic, and epidemiologic benefits of TB screening, this work may enable the field to move beyond ineffective TB screening as a barrier to TBPT and improved outcomes of PLHIV.